NSAID are very widely used in clinical medicine. There is a very large number of drugs in this group including such compounds as aspirin, indomethacin, Diclofenac, Fenoprofen, flufenamic acid, mefenamic acid, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam and sulindac. Although compounds with many different structures come into this class it is believed that their common biological mechanism of action is inhibition of the formation of prostaglandins (PGs). The drugs can produce a very wide range of side effects, the most common and consistent of which is gastro-intestinal bleeding. It is believed that the majority of these side effects, including the bleeding, result from the inhibition of PG synthesis. Although they are implicated in inflammation, PGs have many desirable actions, including a poorly understood cytoprotective effect. PGs of the 1-series, derived from DGLA, have particularly desirable actions but unfortunately NSAID inhibit formation of these PGs as well as the 2-series PGs and other compounds, of part desirable, part undesirable effect, formed from arachidonic acid.
The outline of production of 1-series and 2-series PGs in the body is believed to be as shown in the following diagram: ##STR1##
The broad outline of this pathway is well known, and it brings out clearly that a major function of essential fatty acids is to act as precursors for prostaglandins, 1-series PGs being formed from DGLA and 2-series PGs from arachidonic acid. Further, it has recently been found that the 22:4 n-6 acid produced from arachidonic acid gives rise to a series of homo-2-series PGs, though their importance is as yet unknown.
DGLA is the key substance. GLA is almost completely and very rapidly converted in the body to DGLA and so for practical purposes the oral administration of DGLA and GLA amounts to the same thing. DGLA can be converted to a storage form or to PGs of the 1-series or, through arachidonic acid, to PGs of the 2-series.
Considering dietary requirements, it is well known, for example, that linoleic acid cannot be made by the body and so must be taken in the diet. However, it has been generally thought that the body can metabolise linoleic acid to all the other n-6 acids and therefore that provided linoleic acid intake is adequate, no lack of the other n-6 acids will be found.
In previous patent applications (for example, Published European Patent Application No. A 0 003 407, U.S. Pat. No. 4,273,763; Published European Patent Application No. A 0 004 770, U.S. Pat. No. 4,309,415; Published European Patent Application No. 0 019 423, U.S. Pat. No. 4,388,324) it has, however been pointed out that the first enzyme in the pathway, the delta-6 desaturase which, for example, converts linoleic acid to gamma-linolenic acid, is not fully effective in a variety of conditions. The administration of gamma-linolenic acid or dihomo-gamma-linolenic acid or both has been suggested and has been successful in treating a number of clinical conditions.
In the above patent applications attention is primarily paid to the function of essential fatty acids in prostaglandin (PG) metabolism and in particular to their role in securing a proper balance between 1-series and 2-series PGs.
We are, however, becoming increasingly aware of the significance of the essential fatty acids in themselves, in which considerable general interest has been shown in recent years, primarily in the acids of the n-6 series both as such and in relation to prostaglandin metabolism, but also in the acids of the n-3 series. The n-6 acids in particular are required in the body for the structure of membranes in and around cells, being believed to be necessary for maintaining normal flexibility, fluidity and permeability of such membranes.
The pathways of metabolism of the n-6 essential fatty acids and the related n-3 acids sharing, it is believed, common enzymes in the two pathways, are:
______________________________________ n-6 n-3 ______________________________________ ##STR2## ##STR3## ##STR4## ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11## 22:5 delta-4,7,10,13,16 22:6 delta-4,7,10,13,16,19 ______________________________________
The pathways are not normally reversible nor, in man, are n-3 and n-6 series acids interconvertible.
The acids, which naturally are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19 docosahexaenoic acid, but numerical designation such as, correspondingly, 18:2 n-6 or 22:6 n-3 is convenient. Initials, for example, DHA for 22:6 n-3 (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid. It was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
In the body, the n-3 acids are metabolised preferentially and as a result, in plasma for example, levels of alpha-linolenic acid (18:3 n-3) are low and 18:4 n-3 and 20:4 n-3 are in trace amounts only. In contrast the n-6 acids are normally present in moderate amounts, though gamma-linolenic acid (GLA) is at low levels, being apparently converted to dihomo-gamma-linolenic acid (DGLA) more rapidly than its relatively slow production from linoleic acid. In both series the elongation stages in the metabolic pathways are much more rapid than the desaturations.
Generally, as appears from the earlier patent applications referred to, and from other publications by the inventor, the actions of the 1-series PGs and other metabolic products derived from DGLA are almost all either desirable or neutral, but the actions of the 2-series PGs and other metabolic products derived from arachidonic acid are very mixed, some being desirable and some being highly undesirable.
Studies of the interactions between the metabolism of the n-6 acids and that of the n-3 acids have shown that elongation reactions (e.g. GLA to DGLA) are highly efficient and there is very little competition either way. In contrast, the two series of fatty acids are in competition in the desaturation processes. The n-3 fatty acids interfere with both delta-6 and delta-5 desaturation in the n-6 series. This competition seems to occur even when the n-3 fatty acid is not actually a substrate for the enzyme concerned. For example, 20:5 n-3 competitively inhibits the delta-6 desaturation forming GLA from linoleic acid and overall the presence of n-3 fatty acids in a combination leads to some inhibition of the conversion of DGLA to arachidonic acid by the delta-5 desaturase. As a result of the presence of n-3 EFAs, the efficiency of either GLA or DGLA in increasing the ratio of DGLA products (1-series PGs) to arachidonic acid products (2-series PGs) will therefore be increased.